Studies of limitin for prevention of bone resorption in bacterial periodontitis

限制素预防细菌性牙周炎骨吸收的研究

• 批准号: 16591836
• 负责人: SATO Takuya
• 金额: $ 2.24万
• 依托单位: Meikai University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2004
• 资助国家: 日本
• 起止时间: 2004 至 2005
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-16591836/
• 关键词: limitin; osteoclasts; periodontitis; bone resorption; B細胞

Periodontitis is a bacterial disease and causes tooth loss due to alveolar bone resorption. Immunological reaction due to periodontitis, that is necessary for prevention of systemic infection of the bacteria, results in excessive osteoclastogenesis. Therefore, it is important for treatment of periodontitis to inhibit osteoclastogenesis without diminishing immunological reactions. Limitin is a type-I interferon (IFN) like cytokine and known to stimulate immune responses. Since the other type-I IFN, IFN-beta, inhibits osteoclastogenesis, I hypothesized that limitin also could prevent osteoclastogenesis with stimulatory effects on immune systems. In this project, I studied the effects of limitin on osteoclastogenesis and the mechanism of the effects. I found that limitin strongly inhibits osteoclastogenesis in vitro cultures. On the other hand, limitin stimulated productions of inflammatory cytokines, such as TNF-alpha and RANKL, by CD3-activated T cells. When explored the mechanism of the inhibitory effect of limitin on osteoclastogenesis, I found that limitin decreases c-fos content in osteoclast precursors and stimulates PKR mRNA expression, which is known to be up-regulated in virul infection and to inhibit protein synthesis. Limitin also inhibited transcription of NFATc1 that is a master gene of osteoclastogenesis and is activated by a combination of transcription factors including c-fos. When PKR mRNA was decreased by siRNA technique, limitin did not diminished c-fos content and osteoclastogenesis. These data suggest that limitin inhibits osteoclastogenesis via PKR-dependent inhibition of c-fos synthesis. Limitin is a potential therapeutic factor for prevention of bone loss in periodontal diseases.

牙周炎是一种细菌性疾病，会因牙槽骨吸收而导致牙齿脱落。牙周炎引起的免疫反应是预防细菌全身感染所必需的，会导致破骨细胞生成过多。因此，在不减少免疫反应的情况下抑制破骨细胞生成对于牙周炎的治疗很重要。 Limitin 是一种类似 I 型干扰素 (IFN) 的细胞因子，已知可以刺激免疫反应。由于另一种 I 型干扰素 IFN-β 会抑制破骨细胞生成，因此我推测 limitin 也可以通过对免疫系统的刺激作用来阻止破骨细胞生成。在这个项目中，我研究了 limitin 对破骨细胞生成的影响及其影响机制。我发现 limitin 在体外培养物中强烈抑制破骨细胞生成。另一方面，Limitin 刺激 CD3 激活的 T 细胞产生炎性细胞因子，例如 TNF-α 和 RANKL。在探索limitin对破骨细胞生成的抑制作用机制时，我发现limitin降低破骨细胞前体中的c-fos含量并刺激PKR mRNA表达，已知PKR mRNA表达在病毒感染中上调并抑制蛋白质合成。 Limitin 还抑制 NFATc1 的转录，NFATc1 是破骨细胞生成的主基因，并由包括 c-fos 在内的转录因子组合激活。当通过 siRNA 技术减少 PKR mRNA 时，Limitin 并未减少 c-fos 含量和破骨细胞生成。这些数据表明 limitin 通过 PKR 依赖性抑制 c-fos 合成来抑制破骨细胞生成。 Limitin 是预防牙周病骨质流失的潜在治疗因子。